Despite declining mortality rates, breast cancer ranks second among cancer-related deaths of women. Neoadjuvant chemotherapy is increasingly used to shrink tumors prior to surgery and enable breast conservative approaches; however, long-term survival remains poor, in part due to limited efficacy of cytotoxic drugs that fail to completely eliminate metastatic cells. Thus, these patients have an unmet medical need since there is no known effective therapy that improves outcome. While breast cancer has not historically been linked to underlying inflammation or infection, it exhibits tumor-associated inflammation marked by infiltration of leukocytes into developing tumors where increases in some immune cell subsets in neoplastic stroma parallels disease progression. In the majority of cases however, the natural immunity to cancer that is present is not protective, but instead fosters disease progression. Studies in transgenic mouse models of mammary carcinogenesis have revealed that tumor-associated macrophages (TAMs) promote tumor growth and enhance pulmonary metastasis by high-level expression of epidermal growth factor (EGF) and activation of EGF-regulated signaling in mammary epithelial cells (MECs) critical for invasive tumor growth and metastatic dissemination. We recently reported that interleukin (IL)-4-expressing TH2 CD4+ T cells promote invasion and metastasis of mammary adenocarcinomas by directly regulating TAM phenotype, bioeffector function and EGF expression, that in turn regulate invasive tumor growth, presence of circulating tumor cells (CTCs) and metastasis. These data correlate with clinical findings revealing that breast cancers evade anti-tumor immunity by inflammatory TH2 and regulatory T (Treg) cell responses. Based on these data, we investigated whether blockade of IL4 signaling and neutralization of TH2 immunity altered efficacy of cytotoxic therapy. We found that Paclitaxel-treated tumor-bearing PyMT transgenic mice deficient for IL4 receptor alpha (PyMT/IL4R1) exhibited increased latency to endpoint (primary tumor size) accompanied by increased presence of CD8+ lymphocytes in tumors. Based on these exciting findings and compelling clinical data, the goal of our studies is to assess the hypothesis that an IL4/13-regulated axis functionally regulates pro-tumor immunity in breast cancers and thereby fosters cancer cell escape from protective anti-tumor immune programs. To evaluate this hypothesis, we will block the activities of the type II cytokines IL4 and IL13 and their type I and II receptors and determine which component of the IL4/IL13-axis represents the best candidate for anti-cancer therapy. Blockade of candidates will be complemented by evaluating anti-tumor immune responses to standard of care cytotoxic therapies, alone or in combination with targeted blockade of EGF receptor (EGFR) or colony stimulating factor (CSF)-1 receptor (CSF1R) kinases. These studies will reveal therapeutic strategies to neutralize tumor-promoting TH2-type signaling in breast cancers, that when combined with cytotoxic- or targeted therapy, engender productive cytotoxic responses and durable tumor regression. PUBLIC HEALTH RELEVANCE: The major goal of our project is to assess the hypothesis that an IL4/13-regulated axis functionally regulates pro-tumor immunity in breast cancers and thereby fosters cancer cell escape from protective anti-tumor immune programs. Our studies are designed to reveal therapeutic strategies to neutralize tumor-promoting TH2-type signaling in breast cancers, that when combined with cytotoxic- or targeted therapy, engender productive cytotoxic responses and durable tumor regression.